Purine agonists prevent trophic changes caused by sympathetic denervation

Surgical denervation of the lateral saphenous vein of the dog causes marked extraneuronal changes, both of a morphological and functional type. In an attempt to investigate the factor(s) responsible for the trophic effects exerted by the sympathetic innervation on the dog saphenous vein we studied the effects of noradrenaline, adenosine, inosine and N-ethylcarboxamidoadenosine (NECA) on vascular tissue after sympathetic denervation. The saphenous vein was denervated using either surgical or chemical (6-hydroxydopamine, 6-OHDA) methods. Noradrenaline (0.1 microgram/kg per h), adenosine (10 micrograms/kg per h), inosine (10 micrograms/kg per h) or NECA (0.1 microgram/kg per h) were delivered continuously for 5 days through Alzet minipumps connected to the vein. 6-OHDA-induced denervation resulted in morphological changes similar to those described for surgical denervation. Smooth muscle cells and fibroblasts showed ultrastructural signs of increased synthetic activity and their size was significantly increased. In confirmation of earlier studies, constant i.v. infusions of noradrenaline did not prevent the morphological changes induced by denervation. Adenosine prevented the morphological changes induced by chemical or surgical denervation. Similarly to adenosine, infused NECA prevented the structural consequences of denervation. In contrast, inosine did not prevent the changes caused by surgical denervation. The results are compatible with an involvement of purines in the trophic effects of sympathetic innervation. Moreover, the effects of adenosine do not appear to be mediated by inosine.     

A study of the neuronal and non-neuronal stores of dopamine in rat and rabbit kidney.

The present study has examined the effects of 6-hydroxydopamine (6-OHDA) alone and in combination with pargyline, desipramine and GBR 12909 and denervation as induced by occlusion of the renal artery (RAO) on the endogenous dopamine (DA) and noradrenaline (NA) contents in rat and rabbit renal tissues; the effects of chemical denervation on catecholamine levels in the left ventricle were also studied. In rat and rabbit renal medulla and rat renal cortex, 6-OHDA and pargyline plus 6-OHDA selectively reduced NA (85-92% reduction) without a parallel decrease in DA tissue content (19-27% reduction). This 6-OHDA- and pargyline plus 6-OHDA-insensitive DA pool was found to be resistant to denervation as induced by RAO. The NA-depleting effect of 6-OHDA in these renal areas was found to be prevented by the previous administration of desipramine, but not with that of GBR 12909. In the rabbit renal cortex, 6-OHDA selectively reduced NA (90% reduction) without a parallel depletion of DA (20% reduction); previous treatment with pargyline abolished this selectivity. Again, only desipramine, but not GBR 12909, was found to prevent the NA and DA depleting effect of 6-OHDA in the rabbit renal cortex. Denervation induced by RAO was also found to produce a parallel depletion of DA and NA tissue levels in this renal area. In the left ventricle, 6-OHDA alone or in combination with pargyline produced a parallel depletion of DA and NA tissue levels (79-88% reduction) in both species. These results provide evidence against the presence of independent dopaminergic neurones in rat and rabbit kidney and suggest that in rat and rabbit renal medulla and rat renal cortex most of DA is stored in a non-neuronal compartment; in rabbit renal cortex some of the DA appears to be located in noradrenergic neurones, in a store different from that which contains NA.     

The effect of selective noradrenergic lesions upon the stimulation by noradrenaline of inositol phospholipid breakdown in rat hippocampal miniprisms

The breakdown of inositol phospholipid (PI) stimulated by hippocampal noradrenaline in rat miniprisms in vitro was used as an index of alpha 1-adrenoceptor function after selective noradrenergic denervation. Selective denervation was produced by microinjections of 6-hydroxydopamine (6-OHDA) into either the dorsal noradrenergic bundle (DNAB) or the locus coeruleus (LC), or by systemic treatment with the noradrenergic neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine). Fourteen days after these treatments, there was a large depletion of cortical noradrenaline but no change in the stimulation of hippocampal PI breakdown by noradrenaline. It is concluded that selective noradrenergic denervation under the conditions used here does not lead to hippocampal alpha 1-adrenoceptor supersensitivity as assessed by noradrenaline-stimulated PI breakdown.     

In vivo effects of benztropine and nomifensine on dopamine and noradrenaline terminals in rat brain

6-Hydroxydopamine (6-OHDA) was given intracerebroventricularly, 200 μg to rats with weight 200–250 g. After 14 days dopamine was measured in the corpus striatum and noradrenaline in the rest of the forebrain. Dopamine decreased to 46% and noradrenaline to 23% of the control values. 4 different drugs, benztropine (1, 5 and 25 mg/kg), nomifensine (10 mg/kg), desipramine (25 mg/kg) and amphetamine (5 mg/kg) were given i.p. 30 min before or 15 min after the 6-OHDA to see if they could prevent the depletion of dopamine and nor-adrenaline. Nomifensine, desipramine and, to a lesser degree, amphetamine prevented the depletion of noradrenaline when given before 6-OHDA, and nomifensine also had some effect when given after 6-OHDA. Nomifensine and amphetamine had an effect on the dopamine content when given both before and after 6-OHDA. Desipramine had no effect on dopamine. The largest dose of benztropine had a small effect on dopamine when given after but not when given before 6-OHDA.The results may in an indirect way give some information about the in vivo action of the drugs on the release and uptake of catecholamines in the brain. Thus it is concluded that amphetamine, desipramine and nomifensine all had an effect on the uptake mechanism in noradrenergic terminals and that in addition nomifensine had a releasing effect on these terminals. Amphetamine and nomifensine but not desipramine both inhibited uptake and provoked the release of dopamine in the dopaminergic terminals. The releasing effect of benztropine on the dopamine terminals may have been too small to have clinical relevance.     

Lonicera japonica THUNB. protects 6-hydroxydopamine-induced neurotoxicity by inhibiting activation of MAPKs, PI3K/Akt, and NF-κB in SH-SY5Y cells

In this study, we investigated the neuroprotective effects of Lonicera japonica THUNB. extract (LJ) on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. We found that LJ significantly increased cell viability decrease, lactate dehydrogenase release (LDH), morphological changes, nuclear condensation, fragmentation, and reactive oxygen species (ROS) production induced by 6-OHDA in SH-SY5Y cells. The cytoprotection afforded by pretreatment with LJ was associated with increases of the glutathione (GSH) level, superoxide dismutase (SOD) activity, and catalase (CAT) activity in 6-OHDA-induced SH-SY5Y cells. In addition, LJ strikingly inhibited 6-OHDA-induced mitochondrial dysfunctions including reduction of mitochondria membrane potential (MMP) and activation of cleaved poly-ADP-ribose polymerase (PARP), cleaved caspase-3, cleaved caspase-9, increased Bax, as well as decreased Bcl-2 and Bcl-xL. Additionally, LJ dramatically attenuated 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2), and phosphoinositide 3-kinase (PI3K)/Akt. Meanwhile, LJ counteracted nuclear factor-κB (NF-κB) activation by blocking its translocation to the nucleus. These findings suggest that LJ has a potent anti-parkinsonism; this effect was mediated, at least in part, by inhibition of neurotoxicity, apoptotic cascade events, and oxidative stress via activation of MAPKs, PI3K/Akt, and NF-κB.     

The effect of 6-hydroxydopamine on the antinociceptive action of oxotremorine

Mice received intraventricular 6-hydroxydopamine (6-OHDA) to deplete brain noradrenaline (NA) and dopamine (DA). 6-OHDA reduced the reaction time of mice to a nociceptive stimulus (hot plate) and attenuated the antinociceptive action of oxotremorine. The administration of 6-OHDA to desipramine treated mice prevented both the loss of cerebral NA and the antogonism of oxotremorine's antinociceptive action. The administration of 6-OHDA to pargylinetreated mice increased the depletion of cerebral DA, but the antagonism of oxotremorine's antinociceptive action persisted. Catecholamines were measured in mouse brain at intervals from 1 h to 3 days after administration of 6-OHDA. DA levels failed to correlate with either the reduction in the hot plate reaction time or the antagonism of oxotremorine analgesia, whereas these effects were usually accompanied by a loss of brain NA. Centrally acting DA agonists failed to restore oxotremorine's antinociceptive action in 6-OHDA-treated mice. Intraventricular administration of the acetylcholine synthesis inhibitor triethylcholine to mice did not effect the antinociceptive action of oxotremorine. It is concluded that the antinociceptive action of oxotremorine in mice is initiated by stimulation of muscarinic receptors and involves noradrenergic neurones.     

The effects of chemical sympathectomy on dopamine, noradrenaline and adrenaline content in some peripheral tissues.

Dopamine, noradrenaline (NA) and adrenaline (Ad) depletion by 6-hydroxydopamine (6-OHDA) and pargyline plus 6-OHDA was investigated in the cat left ventricle, mesenteric and renal arteries, renal cortex, renal medulla and adrenal medulla. Catecholamine concentrations in plasma were also analyzed in these two experimental conditions. 6-OHDA alone or in combination with pargyline induced parallel decreases of NA and dopamine contents in the left ventricle. In the main trunk and proximal branches of the mesenteric artery and renal artery 6-OHDA selectively reduced NA without a parallel decrease in dopamine content. Previous treatment with pargyline abolished this selectivity. In the kidney of control animals, dopamine content was greater than could be attributed to its presence only in noradrenergic neurones. In the renal cortex 6-OHDA reduced significantly dopamine and NA contents, and in the renal medulla only NA levels were decreased by this drug. Pargyline plus 6-OHDA did not deplete the NA content either in the renal cortex or in the renal medulla, and only reduced significantly the dopamine content in the renal cortex. NA concentrations in plasma were increased by pargyline plus 6-OHDA whilst Ad remained unaffected. In the adrenal medulla only NA content was reduced either by 6-OHDA or pargyline plus 6-OHDA. The present findings suggest a NA-independent dopamine pool in both segments of the mesenteric artery and renal artery but not in the left ventricle.     

Effect of neonatal 6-hydroxydopamine treatment on the blood pressure response to noradrenaline and tyramine in rats

Neonatal treatment of rats with 6-hydroxydopamine (6-OHDA) caused a permanent depletion of noradrenaline (NA) in the heart and the spleen, but not in the adrenals. In 10–12 week old animals, anesthetized with pentobarbital, sensitivity of the pressor response to various doses of i.v. administered NA increased 5-fold whereas the pressor response to i.v. administered tyramine was greatly diminished; the response to tyramine was further reduced after adrenalectomy, but not in controls. These results suggest that the pressor responses evoked by tyramine and NA can be used as a test for functional sympathetic denervation after 6-OHDA treatment.     

Angiotensin converting enzyme inhibition prevents trophic and hypertensive effects of an antagonist of adenosine receptors

The continuous infusion of 1,3-dipropyl-8-sulfophenylxanthine (DPSPX), a non-selective antagonist of adenosine receptors, causes hypertension and marked cardiovascular structural changes in Wistar rats. Adenosine inhibits noradrenaline and renin release. We investigated the effects of sympathetic denervation, evaluated renin activity and the influence of angiotensin converting enzyme inhibition in DPSPX-treated rats. Captopril was given (30 or 100 mg kg(-l) day(-l); p.o.) from day -l to day 28. On day 0, constant infusions of DPSPX (90 microg kg(-l) h(-l); i.p.) or vehicle were started. On day 28, fragments of the left ventricle, mesenteric and tail arteries were processed for morphological studies. Plasma renin activity was increased in DPSPX-treated animals. Sympathetic denervation delayed and partially prevented blood pressure rise. Angiotensin converting enzyme inhibition prevented DPSPX-induced hypertension and morphological changes. Our results, although pointing to the involvement of the sympathetic system, suggest that other mechanisms are involved. We could not differentiate between the trophic and anti-hypertensive effects of angiotensin converting enzyme inhibition.     

Protective effects of octacosanol on 6-hydroxydopamine-induced Parkinsonism in rats via regulation of ProNGF and NGF signaling

Aim:

To investigate the protective effects of octacosanol in 6-hydroxydopamine-induced Parkinsonian rats and find whether octacosanol has effects on pro nerve growth factor (pro-NGF), NGF and the downstream effector proteins.

Methods:

Behavioral tests, enzymatic assay, tyrosine hydroxylase immunohistochemistry, TUNEL and Western blot were used to investigate the effects of octacosanol in this rat model of PD.

Results:

Oral administration of octacosanol (35–70 mg/kg, po for 14 d) significantly improved the behavioral impairments in rats induced by 6-OHDA and dose-dependently preserved the free radical scavenging capability of the striatum. Octacosanol treatment also effectively ameliorated morphological appearances of TH-positive neuronal cells in nigrostriatal systems and decreased the apoptotic cells induced by 6-OHDA in striatum. In addition, octacosanol strikingly blocked the 6-OHDA-induced increased expression of proNGF-p75NTR-sortilin death signaling complex and its downstream effector proteins. Meantime, octacosanol prevented the decreased levels of NGF, its receptors TrkA and p-Akt which together mediated the cell survival pathway.

Conclusion:

The findings implicated that the anti-parkinsonism effects afforded by octacosanol might be mediated by its neuro-microenvironment improving potency through retrieving the ratios of proNGF:NGF and the respective receptors p75NTR:TrkA in vivo. Due to its excellent tolerability and non-toxicity, octacosanol may be a promising agent for PD treatment.     

培高利特对帕金森病大鼠保护作用的实验研究

目的　探讨多巴胺受体激动剂培高利特 (pergolide)对帕金森病 (PD)模型大鼠的抗氧化作用及其机制。方法　Wistar大鼠随机分为 4组 (对照组和 3个实验组 ) ,实验组预先于腹腔内分别注射培高利特 (1 0mg·kg-1)、选择性D2 受体拮抗剂氨黄酰基苯甲酰胺化合物 (Sulpiride ,2 5mg·kg-1)及培高利特 +Sulpiride。各组预处理均 1次 /天 ,连续 7d后 ,每组大鼠各取 6只分离纹状体 ,测定抗氧化物SOD及GSH活性。各组所剩大鼠则通过立体定位注射 6 羟基多巴胺 (6 OHDA)制作PD模型 ,两周后比较各组阿朴吗啡诱导的旋转行为 ,并取损伤侧纹状体测定多巴胺 (DA)及其代谢产物多巴克 (DOPAC)、高香草酸 (HVA)的含量。结果　大鼠预先连续注射培高利特 7天 ,可明显增强纹状体SOD及GSH的活性 (P <0 0 5 ) ,并对抗 6 OHDA损伤后纹状体DA及其代谢产物含量的下降 (P <0 0 1) ,降低阿朴吗啡诱导的旋转行为 (P <0 0 5 )。而同时应用Sulpiride可抑制培高利特的促纹状体抗氧化作用 ,并消除其对DA能神经元的保护效应。结论　培高利特可通过增加纹状体抗氧化能力 ,对纹状体DA能神经元提供保护作用 ,其机制可能主要与刺激DAD2 受体有关。     

IGF-I receptor signaling pathway is involved in the neuroprotective effect of genistein in the neuroblastoma SK-N-SH cells

Genistein, an isoflavone naturally found in soy products, displays estrogenic properties. Our previous study clearly demonstrated that genistein can activate the insulin-like growth factor-I receptor (IGF-IR) signaling pathway in human breast cancer MCF-7 cells. The present study aims to test the hypothesis that the IGF-I receptor signaling pathway is involved in the neuroprotective effects of genistein in neuroblastoma SK-N-SH cells. Our results revealed that pretreatment with genistein resulted in an enhancement in the survival of human neuroblastoma SK-N-SH cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. 6-OHDA arrested the cells at G(0)G(1) phase and prevented S phase entry. Genistein pretreatment could reverse the cytostatic effect of 6-OHDA on cell cycle. The decreased mitochondrial membrane potential induced by 6-OHDA could be also reversed by genistein pretreatment. These effects could be completely blocked by co-treatment with JB-1, which is the specific antagonist of the IGF-I receptor. Furthermore, genistein pretreatment restored the 6-OHDA-induced up-regulation of Bax and down-regulation of Bcl-2 mRNA and protein expression. Genistein treatment alone could significantly increase the phosphorylation level of MEK and induce ERE luciferase activity. Co-treatment with IGF-I could enhance the effect of genistein on cell proliferation and MEK phosphorylation. This study provides the first evidence that genistein has neuroprotective effects against 6-OHDA-induced neurotoxicity in SK-N-SH cells and activation of the IGF-I receptor signaling pathway might be involved in actions of genistein.     

6-羟基多巴胺诱导PC12细胞释放谷氨酸及死亡不受Ⅰ组亲代谢型谷氨酸受体配基的影响(英文)

目的:探讨Ⅰ组亲代谢型谷氨酸受体(mGluR)配基对6-羟基多巴胺(6-OHDA)诱导的PC12细胞死亡及谷氨酸(Glu)释放的影响。方法:培养PC12细胞,以100μmol/LⅠ组mGluR激动剂(RS)-3,5-dihydroxyphenylglycine(DHPG)和拮抗剂DL-2-amino-3-phosphonopropionic acid(DL-AP3)预先剌激细胞1h,再加入6-OHDA100μmol/L共孵育24h,显微镜下观察细胞形态变化,用TUNEL法检测凋亡细胞,用噻唑蓝(MTT)法检测细胞存活率,并用高效液相色谱检测Glu的释放量。结果:6-OHDA 降低PC12细胞存活率(P<0.01),其诱导的Glu释放呈浓度和时间依赖性。Ⅰ组mGluR配基不能减少6-OHDA引起的PC12细胞死亡,也不影响6OHDA引起的Glu释放量。结论:Ⅰ组mGluR配基对6-OHDA引起死亡的PC12细胞无保护作用。     

Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats

The present study was undertaken to investigate the neuroprotective effects of resveratrol on 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease in rats. 6-OHDA-induced Parkinson's disease rat model involves chronic inflammation, mitochondrial dysfunction, and oxidative stress, and the loss of the dopaminergic neurons in the substantia nigra is the predominant lesion. Resveratrol has been shown to have anti-inflammatory actions, and thus was tested for its beneficial effects using 6-OHDA-induced Parkinson's disease rat model. Adult Sprague–Dawley (SD) rats were unilaterally injected with 6-OHDA (5 µg/2 µl) into the right striatum, and the striatum damage was assessed by rotational test, ultrahistopathology, and molecular alterations. Resveratrol (10, 20 and 40 mg/kg) was then given orally to Parkinson's disease rats, daily for 10 weeks to examine the protective effects. Rotational test (turns of rats) showed that resveratrol significantly attenuated apomorphine-induced turns of rats in 6-OHDA-injuried Parkinson's disease rat model as early as two weeks of administration. Ultrastructural analysis showed that resveratrol alleviated 6-OHDA-induced chromatin condensation, mitochondrial tumefaction and vacuolization of dopaminergic neurons in rat substantia nigra. Furthermore, resveratrol treatment also significantly decreased the levels of COX-2 and TNF-α mRNA in the substantia nigra as detected by real-time RT-PCR. COX-2 protein expression in the substantia nigra was also decreased as evidenced by Western blotting. These results demonstrate that resveratrol exerts a neuroprotective effect on 6-OHDA-induced Parkinson's disease rat model, and this protection is related to the reduced inflammatory reaction.     

芍药苷对6羟基多巴胺致PC12细胞损伤的保护作用

目的:探讨芍药苷对6羟基多巴胺(6-OHDA)致大鼠肾上腺嗜铬细胞瘤细胞(PC12)的细胞损伤保护作用及其可能机制.方法:体外培养PC12细胞,用6-OHDA建立细胞损伤模型.MTT和乳酸脱氢酶(LDH)活性测定存活率;RT-PCR检测Bcl-2、Bax的mRNA表达,Hochest33342/PI双染检测细胞凋亡率.结果:25、50、100 μmol·L-1芍药苷可显著减少6-OHDA诱导的PC12细胞凋亡,降低LDH漏出率,增加Bcl-2 mRNA和减少Bax mRNA表达.结论:芍药苷可显著减少6-OHDA诱导的PC12细胞凋亡,其作用机制可能与调节Bax、Bcl-2表达有关.     

Atypical neuroleptics suppress dopaminergic behavioral supersensitivity

Seven days after bilateral 6-OHDA denervation of the nucleus accumbens locomotor activity was recorded in rats. 6-OHDA lesion strongly enhanced hypermotility induced by apomorphine (1.0 mg/kg IP) as a sign of behavioral dopaminergic supersensitivity. The potency of the classical neuroleptic haloperidol (0.03–0.25 mg/kg IP) to antagonize apomorphine-induced hypermotility was reduced in 6-OHDA-pretreated rats. The atypical neuroleptics sulpiride (5.0–20.0 mg/kg IP), thioridazine (1.0–5.25 mg/kg IP) and clozapine (0.5–2.0 mg/kg IP) and the 5-HT antagonists cyproheptadine (0.2 mg/kg IP) and ritanserin (0.01 mg/kg IP) suppressed the augmented apomorphine response in 6-OHDA-lesioned animals to the level of the apomorphine effect in controls. It is concluded that the model of denervation supersensitivity is capable of differentiating typical and atypical neuroleptics. The abolition of the 6-OHDA-induced increase of the apomorphine hypermotility by the atypical neuroleptics cannot be explained solely by postsynaptic dopamine receptor antagonism. Serotonergic mechanism may be involved in this action.     

An assessment of sympathetic function in isolated tissues from mice given nerve-growth-factor antiserum and 6-hydroxydopamine

1. Experiments were done on isolated tissues from mice injected with 0.9% w/v NaCl solution (saline), 6-hydroxydopamine (6-OHDA), nerve-growth-factor antiserum (NGF-As) or a combination of these agents (NGF-As+6-OHDA).2. Fluorescence histochemistry of vasa deferentia showed clear differences between each of the treatments but no such distinction was possible in cardiac ventricle or intestine.3. Compared with controls, the chronotropic responses of atria to field stimulation were reduced by all three treatments in the order NGF-As<6-OHDA相似文献   

Protective effect of hydrogen sulphide against 6-OHDA-induced cell injury in SH-SY5Y cells involves PKC/PI3K/Akt pathway

BACKGROUND AND PURPOSE

Hydrogen sulphide (H₂S) is a novel neuromodulator. The present study aimed to investigate the protective effect of H₂S against cell injury induced by 6-hydroxydopamine (6-OHDA), a selective dopaminergic neurotoxin often used to establish a model of Parkinson''s disease for studying the underlying mechanisms of this condition.

EXPERIMENTAL APPROACH

Cell viability in SH-SY5Y cells was measured using MTT assay. Western blot analysis and pharmacological manipulation were employed to study the signalling mechanisms.

KEY RESULTS

Treatment of SH-SY5Y cells with 6-OHDA (50–200 µM) for 12 h decreased cell viability. Exogenous application of NaHS (an H₂S donor, 100–1000 µM) or overexpression of cystathionine β-synthase (a predominant enzyme to produce endogenous H₂S in SH-SY5Y cells) protected cells against 6-OHDA-induced cell apoptosis and death. Furthermore, NaHS reversed 6-OHDA-induced loss of tyrosine hydroxylase. Western blot analysis showed that NaHS reversed the down-regulation of PKCα, ε and Akt and the up-regulation of PKCδ in 6-OHDA-treated cells. Blockade of PKCα with Gö6976 (2 µM), PKCε with EAVSLKPT (200 µM) or PI3K with {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 (20 µM) reduced the protective effects of H₂S. However, inhibition of PKCδ with rottlerin (5 µM) failed to affect 6-OHDA-induced cell injury. These data suggest that the protective effects of NaHS mainly resulted from activation of PKCα, ε and PI3K/Akt pathway. In addition, NaHS-induced Akt phosphorylation was significantly attenuated by Gö6976 and EAVSLKPT, suggesting that the activation of Akt by NaHS is PKCα, ε-dependent.

CONCLUSIONS AND IMPLICATIONS

H₂S protects SH-SY5Y cells against 6-OHDA-induced cell injury by activating the PKCα, ε/PI3K/Akt pathway.     

Effect of injections of 6-OHDA into either nucleus accumbens septi or frontal cortex on spontaneous and drug-induced activity

The effect of injections of 6-hydroxydopamine (6-OHDA) into either frontal cortex (FCx) or nucleus accumbens (NAS) on spontaneous, amphetamine and apomorphine photocell cage activity was studied. Both lesions groups had significant noradrenaline depletion in frontal cortex but only the FCx group had significant dopamine depletion in frontal cortex. Whereas NAS 6-OHDA rats exhibited enhanced apomorphine- and decreased amphetamine-activity there were no diffences in activity of the FCx group. 6-OHDA NAS rats also exhibited spontaneous hypoactivity on the third but not the seventh post-operative day; there were no differences in spontaneous activity on either days in the FCx group.In 1975 Kelly, Seviour and Iversen demonstrated that destruction of forebrain dopaminergic terminals induced with injections of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens septi (NAS) attenuated the locomotor response to 1.5 mg/kg d-amphetamine without affecting stereotypy seen at 5.0 mg/kg. In addition, these rats exhibited an enhanced locomotor response to the dopamine receptor agonist apomorphine, an effect thought to reflect receptor supersensitivity induced by dopamine denervation (Ungerstedt, 1971).Biochemical assay data revealed that dopamine levels were significantly reduced both in nucleus accumbens septi (NAS) and olfactory tubercle (OT) but not neostriatum; thus it was concluded that amphetamine- and apomorphine-induced locomotor activity is mediated by the mesolimbic dopamine system.Since then it has become clear that the A10 group of dopamine (DA) cells bodies in the ventral tegmental area (VTA), give rise to dopamine fibres which innervate not only NAS and OT, but also frontal cortex (Bjorklund and Lindvall, 1978). Furthermore, injections of 6-OHDA into NAS deplete frontal cortex dopamine in addition to NAS and OT (Koob, Riley, Smith and Robbins, 1978).Since frontal cortex is generally considered to be part of the limbic system whereas NAS and OT are developmentally akin to basal ganglia (Heimer and Wilson, 1975; Heimer, 1978) it is important to ascertain whether the dopamine innervation of frontal cortex contributes to amphetamine- and apomorphine-induced activity.In the following experiment the effect of apomorphine and amphetamine on activity was assessed in rats with injections of 6-OHDA into either NAS or frontal cortex.